Targeting OGG1 arrests cancer cell proliferation by inducing replication stress

Torkild Visnes, Carlos Benítez-Buelga, Armando Cázares-Körner, Kumar Sanjiv, Bishoy M F Hanna, Oliver Mortusewicz, Varshni Rajagopal, Julian J Albers, Daniel W Hagey, Tove Bekkhus, Saeed Eshtad, Juan Miguel Baquero, Geoffrey Masuyer, Olov Wallner, Sarah Müller, Therese Pham, Camilla Göktürk, Azita Rasti, Sharda Suman, Raúl Torres-RuizAntonio Sarno, Elisée Wiita, Evert J Homan, Stella Karsten, Karthick Marimuthu, Maurice Michel, Tobias Koolmeister, Martin Scobie, Olga Loseva, Ingrid Almlöf, Judith Edda Unterlass, Aleksandra Pettke, Johan Boström, Monica Pandey, Helge Gad, Patrick Herr, Ann-Sofie Jemth, Samir El Andaloussi, Christina Kalderén, Sandra Rodriguez-Perales, Javier Benítez, Hans E Krokan, Mikael Altun, Pål Stenmark, Ulrika Warpman Berglund, Thomas Helleday

Research output: Contribution to journalArticlepeer-review

4 Citations (SciVal)

Abstract

Altered oncogene expression in cancer cells causes loss of redox homeostasis resulting in oxidative DNA damage, e.g. 8-oxoguanine (8-oxoG), repaired by base excision repair (BER). PARP1 coordinates BER and relies on the upstream 8-oxoguanine-DNA glycosylase (OGG1) to recognise and excise 8-oxoG. Here we hypothesize that OGG1 may represent an attractive target to exploit reactive oxygen species (ROS) elevation in cancer. Although OGG1 depletion is well tolerated in non-transformed cells, we report here that OGG1 depletion obstructs A3 T-cell lymphoblastic acute leukemia growth in vitro and in vivo, validating OGG1 as a potential anti-cancer target. In line with this hypothesis, we show that OGG1 inhibitors (OGG1i) target a wide range of cancer cells, with a favourable therapeutic index compared to non-transformed cells. Mechanistically, OGG1i and shRNA depletion cause S-phase DNA damage, replication stress and proliferation arrest or cell death, representing a novel mechanistic approach to target cancer. This study adds OGG1 to the list of BER factors, e.g. PARP1, as potential targets for cancer treatment.

Original languageEnglish
Pages (from-to)12234–12251
JournalNucleic Acids Research
Volume48
Issue number21
Early online date19 Nov 2020
DOIs
Publication statusPublished - 2 Dec 2020

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